tbuckley/cabot-search huggingface dataset:
Evolution of Spatial and Temporal<i>cis-</i>Regulatory Divergence in Sticklebacks
Authors: Katya L Mack, Tyler A Square, Bin Zhao, Craig T Miller, Hunter B Fraser
Journal: Molecular Biology and Evolution (2023)

Abstract Cis-regulatory changes are thought to play a major role in adaptation. Threespine sticklebacks have repeatedly colonized freshwater habitats in the Northern Hemisphere, where they have evolved a suite of phenotypes that distinguish them from marine populations, including changes in physiology, behavior, and morphology. To understand the role of gene regulatory evolution in adaptive divergence, here we investigate cis-regulatory changes in gene expression between marine and freshwater ecotypes through allele-specific expression (ASE) in F1 hybrids. Surveying seven ecologically relevant tissues, including three sampled across two developmental stages, we identified cis-regulatory divergence affecting a third of genes, nearly half of which were tissue-specific. Next, we compared allele-specific expression in dental tissues at two timepoints to characterize cis-regulatory changes during development between marine and freshwater fish. Applying a genome-wide test for selection on cis-regulatory changes, we find evidence for lineage-specific selection on several processes between ecotypes, including the Wnt signaling pathway in dental tissues. Finally, we show that genes with ASE, particularly those that are tissue-specific, are strongly enriched in genomic regions of repeated marine-freshwater divergence, supporting an important role for these cis-regulatory differences in parallel adaptive evolution of sticklebacks to freshwater habitats. Altogether, our results provide insight into the cis-regulatory landscape of divergence between stickleback ecotypes across tissues and during development, and support a fundamental role for tissue-specific cis-regulatory changes in rapid adaptation to new environments.
Engineering of an Osteoinductive and Growth Factor‐Free Injectable Bone‐Like Microgel for Bone Regeneration
Authors: Ramesh Subbiah, Edith Y. Lin, Avathamsa Athirasala, Genevieve E. Romanowicz, Angela S. P. Lin, Joseph V. Califano, Robert E. Guldberg, Luiz E. Bertassoni
Journal: Advanced Healthcare Materials (2023)

Abstract Bone autografts remain the gold standard for bone grafting surgeries despite having increased donor site morbidity and limited availability. Bone morphogenetic protein‐loaded grafts represent another successful commercial alternative. However, the therapeutic use of recombinant growth factors has been associated with significant adverse clinical outcomes. This highlights the need to develop biomaterials that closely approximate the structure and composition of bone autografts, which are inherently osteoinductive and biologically active with embedded living cells, without the need for added supplements. Here, injectable growth factor‐free bone‐like tissue constructs are developed, that closely approximate the cellular, structural, and chemical composition of bone autografts. It is demonstrated that these micro‐constructs are inherently osteogenic, and demonstrate the ability to stimulate mineralized tissue formation and regenerate bone in critical‐sized defects in‐vivo. Furthermore, the mechanisms that allow human mesenchymal stem cells (hMSCs) to be highly osteogenic in these constructs, despite the lack of osteoinductive supplements, are assessed, whereby Yes activated protein (YAP) nuclear localization and adenosine signaling appear to regulate osteogenic cell differentiation. The findings represent a step toward a new class of minimally invasive, injectable, and inherently osteoinductive scaffolds, which are regenerative by virtue of their ability to mimic the tissue cellular and extracellular microenvironment, thus showing promise for clinical applications in regenerative engineering.
Acute hepatitis C virus infection: clinical update and remaining challenges
Authors: Chen-Hua Liu, Jia-Horng Kao
Journal: Clinical and Molecular Hepatology (2023)

Acute hepatitis C virus (HCV) infection is a global health concern with substantial geographical variation in the incidence rate. People who have received unsafe medical procedures, used injection drugs, and lived with human immunodeficiency virus are reported to be most susceptible to acute HCV infection. The diagnosis of acute HCV infection is particularly challenging in immunocompromised, reinfected, and superinfected patients due to difficulty in detecting anti-HCV antibody seroconversion and HCV ribonucleic acid from a previously negative antibody response. With an excellent treatment effect on chronic HCV infection, recently, clinical trials investigating the benefit of direct-acting antivirals (DAAs) treatment for acute HCV infection have been conducted. Based on the results of cost-effectiveness analysis, DAAs should be initiated early in acute HCV infection prior to spontaneous viral clearance. Compared to the standard 8-12 week-course of DAAs for chronic HCV infection, DAAs treatment duration may be shortened to 6-8 weeks in acute HCV infection without compromising the efficacy. Standard DAA regimens provide comparable efficacy in treating HCV-reinfected patients and DAA-naïve ones. For cases contracting acute HCV infection from HCV-viremic liver transplant, a 12-week course of pangenotypic DAAs is suggested. While for cases contracting acute HCV infection from HCV-viremic non-liver solid organ transplants, a short course of prophylactic or pre-emptive DAAs is suggested. Currently, prophylactic HCV vaccines are unavailable. In addition to treatment scale-up for acute HCV infection, practice of universal precaution, harm reduction, safe sex, and vigilant surveillance after viral clearance remain critical in reducing HCV transmission.
Taurocholic acid promotes hepatic stellate cell activation via S1PR2/p38 MAPK/YAP signaling under cholestatic conditions
Authors: Jing Yang, Xujiao Tang, Zhu Liang, Mingzhu Chen, Lixin Sun
Journal: Clinical and Molecular Hepatology (2023)

Background/Aims: Disrupted bile acid regulation and accumulation in the liver can contribute to progressive liver damage and fibrosis. However, the effects of bile acids on the activation of hepatic stellate cells (HSCs) remain unclear. This study investigated the effects of bile acids on HSC activation during liver fibrosis, and examined the underlying mechanisms.Methods: The immortalized HSCs, LX-2 and JS-1cells were used for the in vitro study. in vitro, the adeno-associated viruses adeno-associated virus-sh-S1PR2 and JTE-013 were used to pharmacologically inhibit the activity of S1PR2 in a murine model of fibrosis induced by a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet. Histological and biochemical analyses were performed to study the involvement of S1PR2 in the regulation of fibrogenic factors as well as the activation properties of HSCs.Results: S1PR2 was the predominant S1PR expressed in HSCs and was upregulated during taurocholic acid (TCA) stimulation and in cholestatic liver fibrosis mice. TCA-induced HSC proliferation, migration and contraction and extracellular matrix protein secretion were inhibited by JTE-013 and a specific shRNA targeting S1PR2 in LX-2 and JS-1 cells. Meanwhile, treatment with JTE-013 or S1PR2 deficiency significantly attenuated liver histopathological injury, collagen accumulation, and the expression of fibrogenesis-associated genes in mice fed a DDC diet. Furthermore, TCAmediated activation of HSCs through S1PR2 was closely related to the yes-associated protein (YAP) signaling pathway via p38 mitogen-activated protein kinase (p38 MAPK).Conclusions: TCA-induced activation of the S1PR2/p38 MAPK/YAP signaling pathways plays a vital role in regulating HSC activation, which might be therapeutically relevant for targeting cholestatic liver fibrosis.
Tumor Mutational Burden as a Predictor of Survival with Durvalumab and/or Tremelimumab Treatment in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma
Authors: Sophie Wildsmith, Weimin Li, Song Wu, Ross Stewart, Nassim Morsli, Rajiv Raja, Qu Zhang, Jiabu Ye, Philip He, Jagdish Shetty, Alejandro Yovine, Nicholas Holoweckyj, Katia Real, Jill Walker, Magdalena Wrona, Melissa de los Reyes, Craig Barker, Jessica Whiteley, Robert Haddad, Lisa Licitra, Robert Ferris, Jérôme Fayette, Dan P. Zandberg, Lillian L. Siu, Ricard Mesía
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Biomarkers that predict response to immune checkpoint inhibitors (ICI) in recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) are needed. This retrospective study assessed tumor mutational burden (TMB) and outcomes in the phase II HAWK and CONDOR and phase III EAGLE studies of durvalumab with or without tremelimumab in platinum-resistant R/M HNSCC. Patients and Methods: Tumor samples from HAWK/CONDOR (N = 153) and blood samples from EAGLE (N = 247) were analyzed for TMB. Associations with survival were evaluated for tissue TMB (tTMB) at cutoffs from 10 to 20 mutations/megabase (mut/Mb) and for blood plasma TMB (bTMB) at cutoffs from 8 to 24 mut/Mb. Results: In HAWK/CONDOR, overall survival (OS) with durvalumab with or without tremelimumab was longer for high versus low tTMB: statistically significant differences were observed with durvalumab plus tremelimumab at tTMB ≥ 10 mut/Mb [HR, 0.52 (95% confidence interval, CI, 0.28–0.98)] and tTMB ≥ 12 mut/Mb [HR, 0.46 (95% CI, 0.24–0.86)]. In EAGLE, a significant OS benefit versus chemotherapy was observed with durvalumab and durvalumab plus tremelimumab at bTMB≥16 mut/Mb [HR, 0.39 (95% CI, 0.20–0.76) and 0.38 (95% CI, 0.19–0.78), respectively] but not bTMB &amp;lt; 16 mut/Mb [HR, 0.92 (0.61–1.37) and 0.92 (95% CI, 0.62–1.36), respectively]. A significant progression-free survival benefit was also observed in the ICI arms versus chemotherapy at bTMB ≥ 16 mut/Mb. Conclusions: Findings support TMB as a biomarker for predicting survival in patients with platinum-resistant R/M HNSCC treated with ICIs. The analysis of EAGLE demonstrated that bTMB was predictive of survival with ICI treatment versus chemotherapy in a large, randomized controlled study population.
Functional Homologous Recombination Assay on FFPE Specimens of Advanced High-Grade Serous Ovarian Cancer Predicts Clinical Outcomes
Authors: Sanna Pikkusaari, Manuela Tumiati, Anni Virtanen, Jaana Oikkonen, Yilin Li, Fernando Perez-Villatoro, Taru Muranen, Matilda Salko, Kaisa Huhtinen, Anna Kanerva, Heidi Koskela, Johanna Tapper, Riitta Koivisto-Korander, Titta Joutsiniemi, Ulla-Maija Haltia, Heini Lassus, Sampsa Hautaniemi, Anniina Färkkilä, Johanna Hynninen, Sakari Hietanen, Olli Carpén, Liisa Kauppi
Journal: Clinical Cancer Research (2023)

Deficiency in homologous recombination (HR) repair of DNA damage is characteristic of many high-grade serous ovarian cancers (HGSC). It is imperative to identify patients with homologous recombination-deficient (HRD) tumors as they are most likely to benefit from platinum-based chemotherapy and PARP inhibitors (PARPi). Existing methods measure historical, not necessarily current HRD and/or require high tumor cell content, which is not achievable for many patients. We set out to develop a clinically feasible assay for identifying functionally HRD tumors that can predict clinical outcomes.We quantified RAD51, a key HR protein, in immunostained formalin-fixed, paraffin-embedded (FFPE) tumor samples obtained from chemotherapy-naïve and neoadjuvant chemotherapy (NACT)-treated HGSC patients. We defined cutoffs for functional HRD separately for these sample types, classified the patients accordingly as HRD or HR-proficient, and analyzed correlations with clinical outcomes. From the same specimens, genomics-based HRD estimates (HR gene mutations, genomic signatures, and genomic scars) were also determined, and compared with functional HR (fHR) status.fHR status significantly predicted several clinical outcomes, including progression-free survival (PFS) and overall survival (OS), when determined from chemo-naïve (PFS, P < 0.0001; OS, P < 0.0001) as well as NACT-treated (PFS, P < 0.0001; OS, P = 0.0033) tumor specimens. The fHR test also identified as HRD those PARPi-at-recurrence-treated patients with longer OS (P = 0.0188).We developed an fHR assay performed on routine FFPE specimens, obtained from either chemo-naïve or NACT-treated HGSC patients, that can significantly predict real-world platinum-based chemotherapy and PARPi response. See related commentary by Garg and Oza, p. 2957.
Comparative Genomic Profiling of Second Breast Cancers following First Ipsilateral Hormone Receptor–Positive Breast Cancers
Authors: Elie Rassy, Ingrid Garberis, Alicia Tran-Dien, Bastien Job, Véronique Chung-Scott, Ibrahim Bouakka, Josiane Bassil, Rachel Ferkh, Magali Lacroix-Triki, Fabrizio Zanconati, Fabiola Giudici, Daniele Generali, Etienne Rouleau, Ludovic Lacroix, Fabrice Andre, Barbara Pistilli
Journal: Clinical Cancer Research (2023)

Abstract Purpose: We compared the mutational profile of second breast cancers (SBC) following first ipislateral hormone receptor–positive breast cancers of patient-matched tumors to distinguish new primaries from true recurrences. Experimental Design: Targeted next-generation sequencing using the Oncomine Tumor Mutation Load Assay. Variants were filtered according to their allele frequency ≥ 5%, read count ≥ 5X, and genomic effect and annotation. Whole genome comparative genomic hybridization array (CGH) was also performed to evaluate clonality. Results: Among the 131 eligible patients, 96 paired first breast cancer (FBC) and SBC were successfully sequenced and analyzed. Unshared variants specific to the FBC and SBC were identified in 71.9% and 61.5%, respectively. Paired samples exhibited similar frequency of gene variants, median number of variants per sample, and variant allele frequency of the reported variants except for GATA3. Among the 30 most frequent gene alterations, ARIDIA, NSD2, and SETD2 had statistically significant discordance rates in paired samples. Seventeen paired samples (17.7%) exhibited common variants and were considered true recurrences; these patients had a trend for less favorable survival outcomes. Among the 8 patients with available tissue for CGH analysis and considered new primaries by comparison of the mutation profiles, 4 patients had clonally related tumors. Conclusions: Patient-matched FBC and SBC analysis revealed that only a minority of patients exhibited common gene variants between the first and second tumor. Further analysis using larger cohorts, preferably using single-cell analyses to account for clonality, might better select patients with true recurrences and thereby better inform the decision-making process.
Adenoma Detection Rate and Colorectal Cancer Risk in Fecal Immunochemical Test Screening Programs
Authors: Manuel Zorzi, Giulio Antonelli, Claudio Barbiellini Amidei, Jessica Battagello, Bastianello Germanà, Flavio Valiante, Stefano Benvenuti, Alberto Tringali, Francesco Bortoluzzi, Erica Cervellin, Davide Giacomin, Tamara Meggiato, Erik Rosa-Rizzotto, Diego Fregonese, Manuela Dinca, Gianluca Baldassarre, Paola Scalon, Maurizio Pantalena, Luisa Milan, Gianmarco Bulighin, Daniele Di Piramo, Maurizio Azzurro, Armando Gabbrielli, Alessandro Repici, Douglas K. Rex, Massimo Rugge, Cesare Hassan, Anna Giacomin, Andrea Buda, Deborah Costa, Davide Checchin, Renato Marin, Elisabetta Patarnello, Aldo Ceriani, Ennio Guido, Perla Bertomoro, Nicoletta Merlini, Francesca Murer, Ephrem Ntakirutimana, Luca Benazzato, Maria Cristina Conti Bellocchi, Anna Giacomin, Andrea Buda, Deborah Costa, Davide Checchin, Renato Marin, Elisabetta Patarnello, Aldo Ceriani, Ennio Guido, Perla Bertomoro, Nicoletta Merlini, Francesca Murer, Ephrem Ntakirutimana, Luca Benazzato, Maria Cristina Conti Bellocchi
Journal: Annals of Internal Medicine (2023)

Colorectal cancer (CRC) screening programs based on fecal immunochemical tests (FITs) represent the standard of care for population-based interventions. Their benefit depends on the identification of neoplasia at colonoscopy after FIT positivity. Colonoscopy quality measured by adenoma detection rate (ADR) may affect screening program effectiveness.To examine the association between ADR and postcolonoscopy CRC (PCCRC) risk in a FIT-based screening program.Retrospective population-based cohort study.Fecal immunochemical test-based CRC screening program between 2003 and 2021 in northeastern Italy.All patients with a positive FIT result who had a colonoscopy were included.The regional cancer registry supplied information on any PCCRC diagnosed between 6 months and 10 years after colonoscopy. Endoscopists' ADR was categorized into 5 groups (20% to 39.9%, 40% to 44.9%, 45% to 49.9%, 50% to 54.9%, and 55% to 70%). To examine the association of ADR with PCCRC incidence risk, Cox regression models were fitted to estimate hazard ratios (HRs) and 95% CIs.Of the 110 109 initial colonoscopies, 49 626 colonoscopies done by 113 endoscopists between 2012 and 2017 were included. After 328 778 person-years follow-up, 277 cases of PCCRC were diagnosed. Mean ADR was 48.3% (range, 23% and 70%). Incidence rates of PCCRC from lowest to highest ADR group were 13.13, 10.61, 7.60, 6.01, and 5.78 per 10 000 person-years. There was a significant inverse association between ADR and PCCRC incidence risk, with a 2.35-fold risk increase (95% CI, 1.63 to 3.38) in the lowest group compared with the highest. The adjusted HR for PCCRC associated with 1% increase in ADR was 0.96 (CI, 0.95 to 0.98).Adenoma detection rate is partly determined by FIT positivity cutoff; exact values may vary in different settings.In a FIT-based screening program, ADR is inversely associated with PCCRC incidence risk, mandating appropriate colonoscopy quality monitoring in this setting. Increasing endoscopists' ADR may significantly reduce PCCRC risk.None.
Symptom and Viral Rebound in Untreated SARS-CoV-2 Infection
Authors: Rinki Deo, Manish C. Choudhary, Carlee Moser, Justin Ritz, Eric S. Daar, David A. Wohl, Alexander L. Greninger, Joseph J. Eron, Judith S. Currier, Michael D. Hughes, Davey M. Smith, Kara W. Chew, Jonathan Z. Li, Arzhang Cyrus Javan, Mark Giganti, Lara Hosey, Jhoanna Roa, Nilam Patel, Kelly Colsh, Irene Rwakazina, Justine Beck, Scott Sieg, Courtney Fletcher, William Fischer, Teresa Evering, Rachel Bender Ignacio, Sandra Cardoso, Katya Corado, Prasanna Jagannathan, Nikolaus Jilg, Alan Perelson, Sandy Pillay, Cynthia Riviere, Upinder Singh, Babafemi Taiwo, Joan Gottesman, Matthew Newell, Susan Pedersen, Joan Dragavon, Cheryl Jennings, Brian Greenfelder, William Murtaugh, Jan Kosmyna, Morgan Gapara, Akbar Shahkolahi
Journal: Annals of Internal Medicine (2023)

Although symptom and viral rebound have been reported after nirmatrelvir-ritonavir treatment, the trajectories of symptoms and viral load during the natural course of COVID-19 have not been well described.To characterize symptom and viral rebound in untreated outpatients with mild to moderate COVID-19.Retrospective analysis of participants in a randomized, placebo-controlled trial. (ClinicalTrials.gov: NCT04518410).Multicenter trial.563 participants receiving placebo in the ACTIV-2/A5401 (Adaptive Platform Treatment Trial for Outpatients With COVID-19) platform trial.Participants recorded the severity of 13 symptoms daily between days 0 and 28. Nasal swabs were collected for SARS-CoV-2 RNA testing on days 0 to 14, 21, and 28. Symptom rebound was defined as a 4-point increase in total symptom score after improvement any time after study entry. Viral rebound was defined as an increase of at least 0.5 log10 RNA copies/mL from the immediately preceding time point to a viral load of 3.0 log10 copies/mL or higher. High-level viral rebound was defined as an increase of at least 0.5 log10 RNA copies/mL to a viral load of 5.0 log10 copies/mL or higher.Symptom rebound was identified in 26% of participants at a median of 11 days after initial symptom onset. Viral rebound was detected in 31% and high-level viral rebound in 13% of participants. Most symptom and viral rebound events were transient, because 89% of symptom rebound and 95% of viral rebound events occurred at only a single time point before improving. The combination of symptom and high-level viral rebound was observed in 3% of participants.A largely unvaccinated population infected with pre-Omicron variants was evaluated.Symptom or viral relapse in the absence of antiviral treatment is common, but the combination of symptom and viral rebound is rare.National Institute of Allergy and Infectious Diseases.
Cold Versus Hot Snare Polypectomy for Small Colorectal Polyps
Authors: Li-Chun Chang, Chi-Yang Chang, Chi-Yi Chen, Cheng-Hao Tseng, Peng-Jen Chen, Chia-Tung Shun, Wen-Feng Hsu, Yen-Nien Chen, Chieh-Chang Chen, Tien-Yu Huang, Chia-Hung Tu, Mei-Jyh Chen, Chu-Kuang Chou, Ching-Tai Lee, Po-Yueh Chen, Ming-Shiang Wu, Han-Mo Chiu
Journal: Annals of Internal Medicine (2023)

Background: Although cold snare polypectomy (CSP) is considered effective in reducing delayed postpolypectomy bleeding risk, direct evidence supporting its safety in the general population remains lacking. Objective: To clarify whether CSP would reduce delayed bleeding risk after polypectomy compared with hot snare polypectomy (HSP) in the general population. Design: Multicenter randomized controlled study. (ClinicalTrials.gov: NCT03373136) Setting: 6 sites in Taiwan, July 2018 through July 2020. Participants: Participants aged 40 years or older with polyps of 4 to 10 mm. Intervention: CSP or HSP to remove polyps of 4 to 10 mm. Measurements: The primary outcome was the delayed bleeding rate within 14 days after polypectomy. Severe bleeding was defined as a decrease in hemoglobin concentration of 20 g/L or more, requiring transfusion or hemostasis. Secondary outcomes included mean polypectomy time, successful tissue retrieval, en bloc resection, complete histologic resection, and emergency service visits. Results: A total of 4270 participants were randomly assigned (2137 to CSP and 2133 to HSP). Eight patients (0.4%) in the CSP group and 31 (1.5%) in the HSP group had delayed bleeding (risk difference, −1.1% [95% CI, −1.7% to −0.5%]). Severe delayed bleeding was also lower in the CSP group (1 [0.05%] vs. 8 [0.4%] events; risk difference, −0.3% [CI, −0.6% to −0.05%]). Mean polypectomy time (119.0 vs. 162.9 seconds; difference in mean, −44.0 seconds [CI, −53.1 to −34.9 seconds]) was shorter in the CSP group, although successful tissue retrieval, en bloc resection, and complete histologic resection did not differ. The CSP group had fewer emergency service visits than the HSP group (4 [0.2%] vs. 13 [0.6%] visits; risk difference, −0.4% [CI, −0.8% to −0.04%]). Limitation: An open-label, single-blind trial. Conclusion: Compared with HSP, CSP for small colorectal polyps significantly reduces the risk for delayed postpolypectomy bleeding, including severe events. Primary Funding Source: Boston Scientific Corporation.
Treatment Strategy for Rifampin-Susceptible Tuberculosis
Authors: Nicholas I. Paton, Christopher Cousins, Celina Suresh, Erlina Burhan, Ka Lip Chew, Victoria B. Dalay, Qingshu Lu, Tutik Kusmiati, Vincent M. Balanag, Shu Ling Lee, Rovina Ruslami, Yogesh Pokharkar, Irawaty Djaharuddin, Jani J.R. Sugiri, Rholine S. Veto, Christine Sekaggya-Wiltshire, Anchalee Avihingsanon, Rohit Sarin, Padmasayee Papineni, Andrew J. Nunn, Angela M. Crook
Journal: New England Journal of Medicine (2023)

Tuberculosis is usually treated with a 6-month rifampin-based regimen. Whether a strategy involving shorter initial treatment may lead to similar outcomes is unclear.
Clinical Implications of Negatively Adjudicated Heart Failure Events: Data From the VICTORIA Study
Authors: G. Michael Felker, Rebecca North, Hillary Mulder, W. Schuyler Jones, Kevin J. Anstrom, Mahesh J. Patel, Javed Butler, Justin A. Ezekowitz, Carolyn Lam, Christopher M. O’Connor, Lothar Roessig, Adrian F. Hernandez, Paul W. Armstrong
Journal: Circulation (2023)

possible heart failure.